Document Detail

Suppression of bile acid synthesis, but not of hepatic cholesterol 7alpha-hydroxylase expression, by obstructive cholestasis in humans.
MedLine Citation:
PMID:  11481606     Owner:  NLM     Status:  MEDLINE    
Regulation of bile acid synthesis, a key determinant of cholesterol homeostasis, is still incompletely understood. To elucidate the feedback control exerted on bile acid biosynthesis in humans with obstructive cholestasis, 16 patients with bile duct obstruction were studied. In vivo 7alpha-hydroxylation, reflecting bile acid synthesis, was assayed in 13 of them by tritium release analysis. Serum 27-hydroxycholesterol was determined by gas chromatography-mass spectrometry. In a subgroup, hepatic cholesterol 7alpha-hydroxylase mRNA was assayed by real-time polymerase chain reaction (PCR), enzyme activity was determined by isotope incorporation, and microsomal cholesterol content was assayed by gas chromatography-mass spectrometry. Age-matched control subjects were studied in parallel. Hydroxylation rates were lower in cholestatic patients (108 +/- 33 mg of cholesterol per day, mean +/- SEM; controls: 297 +/- 40 mg/d; P <.01). The reduction was proportional to the severity of cholestasis, and synthetic rates were normalized in 4 subjects restudied after resolution of biliary obstruction. Consistent findings were obtained by analysis of serum 7alpha-hydroxycholesterol levels. On the other hand, hepatic cholesterol 7alpha-hydroxylase mRNA, microsomal enzyme activity, and cholesterol content tended to be increased in cholestasis. Finally, serum 27-hydroxycholesterol levels were slightly reduced in cholestatic subjects and were not related with the severity of the disease. Suppression of in vivo bile acid synthesis with no corresponding reduction in tissue 7alpha-hydroxylase expression and activity is consistent with nontranscriptional, posttranslational levels of regulation; these may play a role in the feedback control of bile acid synthesis in particular conditions. Alteration of the alternate biosynthetic pathway seems unlikely according to the present data.
M Bertolotti; L Carulli; M Concari; P Martella; P Loria; E Tagliafico; S Ferrari; M Del Puppo; B Amati; E De Fabiani; M Crestani; C Amorotti; A Manenti; F Carubbi; A Pinetti; N Carulli
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Hepatology (Baltimore, Md.)     Volume:  34     ISSN:  0270-9139     ISO Abbreviation:  Hepatology     Publication Date:  2001 Aug 
Date Detail:
Created Date:  2001-08-01     Completed Date:  2001-08-23     Revised Date:  2006-11-15    
Medline Journal Info:
Nlm Unique ID:  8302946     Medline TA:  Hepatology     Country:  United States    
Other Details:
Languages:  eng     Pagination:  234-42     Citation Subset:  IM    
Dipartimento di Medicina Interna, Università degli Studi di Modena e Reggio Emilia, Modena, Italy.
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MeSH Terms
Aged, 80 and over
Bile Acids and Salts / antagonists & inhibitors*,  biosynthesis
Cholestasis / metabolism*,  physiopathology
Cholesterol / metabolism
Cholesterol 7-alpha-Hydroxylase / genetics,  metabolism*
Hydroxycholesterols / blood
Liver / enzymology*,  metabolism
Microsomes, Liver / enzymology
Middle Aged
RNA, Messenger / metabolism
Reference Values
Severity of Illness Index
Reg. No./Substance:
0/Bile Acids and Salts; 0/Hydroxycholesterols; 0/RNA, Messenger; 566-26-7/cholest-5-en-3 beta,7 alpha-diol; 57-88-5/Cholesterol; EC 7-alpha-Hydroxylase

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